This invention relates generally to tetracyclic tetrahydroquinoline compounds, and analogues thereof, and pharmaceutically acceptable salt forms thereof, which are selective inhibitors of serine protease enzymes, especially factor VIIa; pharmaceutical compositions containing the same; and methods of using the same as anticoagulant agents for modulation of the coagulation cascade.
The present invention generally relates to compounds that inhibit thrombosis. In particular it is directed to compounds that are selective inhibitors of serine protease enzymes, for example thrombin, factor Xa, factor IXa, factor XIa and factor VIIa. In particular, it relates to compounds that are factor VIIa inhibitors.
Factor VIIa is a plasma serine protease involved in the initiation of blood coagulation. Alone, it processes its substrates factor IX and factor X slowly. In the presence of its cofactor, a membrane protein called tissue factor, proteolytic activity towards its substrates is greatly enhanced. Sufficient quantities of factor IXa and factor Xa are generated by the factor VIIa/tissue factor complex to initiate coagulation. Tissue factor is not normally exposed to factor VIIa in circulating blood, but is widely expressed extravascularly. Vascular rupture results in exposure of factor VIIa to tissue factor, formation of the factor VIIa/tissue factor complex, and initiation of coagulation. See Carson, S. D. and Brozna, J. P. (1993) Blood Coag. Fibrinol. 4:281-292.
The factor VIIa/tissue factor complex initiates blood coagulation by activating factor X to factor Xa, factor IX to factor IXa and additional factor VII to factor VIIa. Ultimately, the activity of factor VIIa induces the conversion of prothrombin to thrombin. Thrombin is a proteolytic enzyzme which occupies a central role in the coagulation process. It converts fibrinogen to fibrin, an essential structural component of the blood clot, and plays a key role in activating other coagulation proteins.
While blood coagulation is a necessary and important part of an organism""s normal functioning (hemostasis), it can sometimes have deleterious effects. For instance, tissue factor exposed by rupture of an atherosclerotic plaque can initiate coagulation in a coronary artery, blocking circulation and inducing a heart attack.
Because of its role in initiate of blood coagulation, it is believed that inhibition of factor VIIa could be useful for treatment or prevention of disease states involving abnormal coagulation, including thrombosis, coronary artery disease, ischemic vascular disease, intravascular clotting, stroke, embolism, etc. Work has accordingly be performed to identify and optimize factor VIIa inhibitors. For example, U.S. Pat. No. 5,859,010 discusses factor VIIa/tissue factor inhibitors that are dihydroxamates having a spacing from 0.37 nm to about 0.77 nm; U.S. Pat. No. 5,843,442 reports monoclonal-type antibodies or antibody fragments possessing inhibitory activity; and, U.S. Pat. No. 5,023,236 presents peptides and peptide derivatives that specifically inhibit the proteolytic active site of serine protease coagulation factor VII/VIIa. WO 2000/35886 discloses bicyclic heterocyclic inhibitors of serine proteases including factor Xa, urokinase-type plasminogen activator, and factor VIIa.
While a number of factor VIIa inhibitors have been discussed in the art, improved inhibitors are always desirable, especially non-peptide inhibitors.
Accordingly, the present invention provides novel tetracyclic tetrahydroquinoline compounds, which are useful as selective inhibitors of serine protease enzymes, especially factor VIIa, or pharmaceutically acceptable salts or prodrugs thereof.
The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
The present invention also provides a method for modulation of the coagulation cascade comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
The present invention also provides a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
The present invention also provides novel tetracyclic tetrahydroquinoline compounds for use in therapy.
The present invention also provides the use of novel tetracyclic tetrahydroquinoline compounds for the manufacture of a medicament for the treatment of a thromboembolic disorder.
These and other embodiments, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that the presently claimed tetracyclic compounds, or pharmaceutically acceptable salt or prodrug forms thereof, are effective factor VIIa inhibitors.